There are over 1.6 million amputees living in the US and it is estimated that 3000 join their ranks each week. Limb amputation results from disease, traumatic accident, birth defects, and warfare, and often is accompanied by chronic pain, impaired locomotion, and inability to conduct bimanual tasks. Limb loss may lead to long-term disability, job loss, and represents a major worldwide health problem. Limb amputation also results in massive cortical reorganization. Understanding the central neurological consequences that follow amputation is crucial for devising therapies and developing alternative strategies to compensate for loss of limb. Incomplete understanding of the effects of forelimb amputation on central nervous system processing limits our ability to ameliorate these deficits or to develop prosthetic devices for restoration of function. Cortical reorganization is often associated with chronic limb pain;by testing hypotheses about the structural and functional bases of brain reorganization, we can hope to better understand and control chronic limb pain. The goals of this proposal are to understand the mechanisms that underlie delayed large-scale cortical reorganization that follows forelimb amputation. The rat forepaw barrel subfield in first somatosensory cortex, ventral posterior lateral nucleus (VPL), thalamic reticular nucleus (RTN), and cuneate nucleus (CN) will serve as our model systems. By using a model system and techniques in which we are expert, we will elucidate the central consequences of forelimb amputation and examine potential mechanisms that underlie cortical reorganization. The objectives of this proposal are: a) test hypotheses that delayed large-scale cortical reorganization results from changes in subcortical circuitry, b) test hypotheses that removal of GABAergic inhibition is a mechanism for cortical reorganization, c) test hypotheses that RTN and CN provide substrates for the delay component in long-term cortical reorganization, and d) test hypotheses that forelimb amputation alters intact cortex and results in deficits in fine movement in the intact limb. The proposal incorporates techniques in physiological brain mapping, microstimulation, anatomical tracing, immunocytochemistry, and in-situ hybridization histochemistry that are routinely used in our laboratories. Four Aims are proposed: Aim 1: Test hypotheses that forelimb amputation results in delayed reorganization in VPL and CN, and reorganization is under GABAergic control. Aim 2: Test hypotheses that forepaw VPL projection neurons that relay new input to FBS also provide the pathway for new input to deafferented cortex. Aim 3: Test hypotheses that RTN provides delayed inhibitory control of VPL. Aim 4: Test hypotheses that forelimb amputation also alters non-deafferented cortex and leads to deficits in fine motor control in the intact limb.